Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
POSTER SESSION 2 – P2.01: BIOLOGY/PATHOLOGY
MARKER FOR PROGNOSIS, PREDICTION –
TUESDAY, DECEMBER 6, 2016
P2.01-081 CDCA3 IS A NOVEL PROGNOSTIC CELL CYCLE PROTEIN
AND TARGET FOR THERAPY IN NON-SMALL CELL LUNG CANCER
Mark Adams 1 , Joshua Burgess 1 , Kathy Gately 2 , Cameron Snell 3 , Derek
Richard 4 , Kenneth O’Byrne 5
1 Translational Research Institute, Institute of Health and Biomedical Innovation,
Woolloongabba/QLD/Australia, 2 Thoracic Oncology Research Group, Trinity College
Dublin/st. James’ Hospital, Dublin/Ireland, 3 Mater Health Services, Brisbane/QLD/
Australia, 4 Translational Research Institute, Institute of Health and Biomedical
Innovation, Woolloongabba/Australia, 5 Cancer & Ageing Research Program,
Princess Alexandra Hospital & Queensland University of Technology, Brisbane/QLD/
Australia
that MFN2 ablation had on A549 cells, as well as identified a few genes whose
expression level associated with clinicopathologic parameters. In addition,
transcriptional factor target enrichment analysis identified E2F as a potential
transcription factor that was deregulated in response to MFN2 deficiency.
(See figures next page)
Background: Lung cancer is the leading cause of cancer-related mortality
worldwide with a 5 year survival rate of 15%. Non-small cell lung cancer
(NSCLC) is the most commonly diagnosed form of lung cancer. Cisplatin-based
regimens are currently the most effective chemotherapy for NSCLC, however,
chemoresistance poses a major therapeutic problem. New and reliable
strategies are required to avoid drug resistance in NSCLC. Cell division cycle
associated 3 (CDCA3) is a key regulator of the cell cycle. CDCA3 modulates this
process by enabling cell entry into mitosis through degradation of the mitosisinhibitory
factor WEE1. CDCA3 itself is also degraded in G1 yet re-expressed
in G2/M phase, to allow successful progression through the cell cycle. Herein,
we describe CDCA3 as a novel prognostic factor in NSCLC and target to
delay or prevent cisplatin resistance in NSCLC. Methods: CDCA3 expression
was investigated in squamous and non-squamous NSCLC using several
approaches including bioinformatic analysis of publicly available datasets,
immunohistochemistry of a tissue microarray and western blot analysis of
matched tumour and normal tissue and NSCLC cell lines. CDCA3 function
in NSCLC was determined using several in vitro assays by siRNA depleting
CDCA3 in a panel of three immortalized bronchial epithelial cell lines (HBEC)
and seven NSCLC cell lines. Results: CDCA3 transcripts and protein levels are
elevated in NSCLC patient tissue and highly expressed in tumour cells relative
to proximal normal cells. High mRNA levels are associated with poor survival
in resected NSCLC. Depletion of CDCA3 in vitro markedly impairs proliferation
in seven NSCLC cell lines by inducing a mitotic cell cycle arrest, ultimately
resulting in p21-dependent cellular senescence. Importantly, silencing of
CDCA3 also greatly sensitises NSCLC cell lines to cisplatin. In line with these in
vitro data, NSCLC patients that have elevated levels of CDCA3 and are treated
with cisplatin have a poorer outcome than patients with reduced levels of
the protein. To improve patient response to cisplatin, we are exploring novel
strategies to suppress CDCA3 expression in tumour cells. Conclusion: Our
data highlight CDCA3 as a novel factor in mediating NSCLC. We propose that
evaluating novel strategies to target CDCA3 may prove a useful strategy is
enhancing the anti-tumour activity of platinum-based chemotherapy and may
ultimately benefit patient outcomes by preventing cisplatin resistance.
Keywords: Cell cycle, non-small cell lung cancer, cisplatin chemotherapy,
prognostic factor
POSTER SESSION 2 – P2.01: BIOLOGY/PATHOLOGY
MARKER FOR PROGNOSIS, PREDICTION –
TUESDAY, DECEMBER 6, 2016
P2.01-082 TRANSCRIPTIONAL PROFILING IDENTIFIED THE ANTI-
PROLIFERATIVE EFFECT OF MITOFUSIN-2 DEFICIENCY AND ITS
RISK IN LUNG ADENOCARCINOMA
Yuqing Lou 1 , Yanwei Zhang 2 , Rong Li 2 , Ping Gu 2 , Liwen Xiong 2 , Hua Zhong 1 ,
Xueyan Zhang 1 , Liyan Jiang 3 , Wei Zhang 2 , Baohui Han 3
1 Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiaotong University,
Shanghai/China, 2 Shanghai Chest Hospital, Shanghai Jiaotong University,
Shanghai/China, 3 Department of Pulmonary Medicine, Shanghai Chest Hospital,
Shanghai Jiaotong University, Shanghai/China
Background: Mitofusin-2(MFN2) was initially identified as a hyperplasia
suppressor in hyper-proliferative vascular smooth muscle cells of
hypertensive rat arteries, which has also been implicated in various cancers.
There exists a controversy in whether it is an oncogene or exerting antiproliferative
effect on tumor cells. Our previous cell cycle analysis and MTT
assay showed that cell proliferation was inhibited in MFN2 deficient A549
human lung adenocarcinoma cells, without investigating the changes in
regulatory network or addressing the underlying mechanisms. Methods: We
performed expression profiling in MFN2 knock-down A549 cells. Furthermore,
we compared the expression profiling of a cohort consisting of 61 pairs of
tumor-normal match samples from The Cancer Genome Atlas(TCGA). Results:
The expression profiling in MFN2 knock-down cells suggested that cancer
related pathways were among the most susceptible pathways to MFN2
deficiency. Next, we teased out the specific pathways to address the impact
S436 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017